PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in women, and mortality from CVD is higher in postmenopausal women (PMW) compared to age-matched men. PMW are at a greater risk for developing hypertension (HTN), a major risk factor for CVD. Furthermore, PMW are more likely to have uncontrolled or resistant HTN despite medication. Functional changes in the microcirculation can be used as an index of future CVD risk; the mechanisms contributing to microvascular dysfunction can be easily assessed using the cutaneous circulation. Endothelin-1 (ET-1) is a potent vasoconstrictor that has been implicated in the development of HTN, and data in animal models indicates ET-1 receptors are modulated by hormones like estradiol and angiotensin II (ANG II). The first aim of this project is to test the hypothesis that ET-1 contributes to vasoconstriction in hypertensive PMW and that ANG II exacerbates the effects of ET-1. The second aim of this project is to test the hypothesis that ET-1 expression along with ET-A and ET-B receptor expression are altered in hypertensive PMW. Our central hypothesis is that hypertensive PMW have greater ET-1 mediated vasoconstrictor tone due to increased ET-1 expression, down-regulation of ET-B receptors on endothelial cells and up-regulation of both ETA and ETB receptors on vascular smooth muscle. We further hypothesize that ANG II exacerbate the increase in ET-1, and the cellular changes ET-A and ET-B receptor expression contribute to the exaggerated constriction with HTN in PMW. We will test our central hypothesis by measuring changes in cutaneous blood flow during intradermal microdialysis infusions of ET-A and ET-B receptor antagonists in normotensive PMW and hypertensive PMW before and after losartan. Endothelial cells and skin punch biopsies will also be obtained directly from normotensive and hypertensive PMW (pre/post losartan) to examine cellular expression of ET-1 and ET-A and ET-B receptors. This comprehensive assessment of ET-1 receptor responses will provide novel information on the mechanisms contributing to vascular dysfunction in hypertensive PMW. Because CVD is the leading cause of death in women and PMW have a higher prevalence of HTN and mortality from CVD, understanding the mechanisms contributing to this higher prevalence in women is of both physiological and clinical importance to develop future preventative and therapeutic strategies for women.